Follicular helper T cells mediate IgE antibody response to airborne allergens

Background: T(H)2 cells have long been believed to play a pivotal role in allergic immune responses, including IgE antibody production and type 2 cytokine-mediated inflammation and pathology. A new T-cell subset, follicular helper T (T-FH) cells, is specialized in supporting B-cell maturation and antibody production. Objective: We sought to investigate the roles of TFH cells in allergic immune responses. Methods: Naive mice were exposed to cytokines or natural allergens through the airways. Development of allergic immune responses was analyzed by collecting draining lymph nodes and sera and by challenging the animals. Cytokine reporter mice and gene-deficient mice were used to dissect the immunologic mechanisms. Results: We observed the development of IL-4-producing T-FH cells and T(H)2 cells in draining lymph nodes after airway exposure to IL-1 family cytokines or natural allergens. T-FH and T(H)2 cells demonstrated unique phenotypes, tissue localization, and cytokine responses. T-FH cells supported the sustained production of IgE antibody in vivo in the absence of other T-cell subsets or even when T(H)2 cell functions were severely compromised. Conversely, conditional deficiency of the master regulator Bcl6 in CD4(+) T cells resulted in a marked reduction in T-FH cell numbers and IgE antibody levels, but type 2 cytokine responses and eosinophilic inflammation in the airways remained unaffected. Conclusion: T-FH cells play critical roles in the regulation of IgE antibody production. Allergic immune responses to airborne allergens likely involve 2 distinct subsets of IL-4-producing CD4(+) T cells, namely T-FH and Th2 cells.